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@ARTICLE{Lee:270998,
author = {O. W. Lee and C. Rodrigues and S.-H. Lin and W. Luo and K.
Jones and D. W. Brown and W. Zhou and E. Karlins and S. M.
Khan and S. Baulande and V. Raynal and D. Surdez and S.
Reynaud and R. A. Rubio and S. Zaidi and S. Grossetête and
S. Ballet and E. Lapouble and V. Laurence and G. Pierron and
N. Gaspar and N. Corradini and P. Marec-Bérard and N.
Rothman and C. L. Dagnall and L. Burdett and M. Manning and
K. Wyatt and M. Yeager and R. Chari and W. M. Leisenring and
A. E. Kulozik and J. Kriebel and T. Meitinger and K. Strauch
and T. Kirchner$^*$ and U. Dirksen and L. Mirabello and M.
A. Tucker and F. Tirode and G. T. Armstrong and S. Bhatia
and L. L. Robison and Y. Yasui and L. Romero-Pérez$^*$ and
W. Hartmann and M. Metzler and W. R. Diver and A. Lori and
N. D. Freedman and R. N. Hoover and L. M. Morton and S. J.
Chanock and T. Grünewald$^*$ and O. Delattre and M. J.
Machiela},
title = {{T}argeted long-read sequencing of the {E}wing sarcoma
6p25.1 susceptibility locus identifies germline-somatic
interactions with {EWSR}1-{FLI}1 binding.},
journal = {The American journal of human genetics},
volume = {110},
number = {3},
issn = {0002-9297},
address = {New York, NY},
publisher = {Elsevier},
reportid = {DKFZ-2023-00351},
pages = {427-441},
year = {2023},
note = {2023 Mar 2;110(3):427-441},
abstract = {Ewing sarcoma (EwS) is a rare bone and soft tissue
malignancy driven by chromosomal translocations encoding
chimeric transcription factors, such as EWSR1-FLI1, that
bind GGAA motifs forming novel enhancers that alter nearby
expression. We propose that germline microsatellite
variation at the 6p25.1 EwS susceptibility locus could
impact downstream gene expression and EwS biology. We
performed targeted long-read sequencing of EwS blood DNA to
characterize variation and genomic features important for
EWSR1-FLI1 binding. We identified 50 microsatellite alleles
at 6p25.1 and observed that EwS-affected individuals had
longer alleles (>135 bp) with more GGAA repeats. The 6p25.1
GGAA microsatellite showed chromatin features of an
EWSR1-FLI1 enhancer and regulated expression of RREB1, a
transcription factor associated with RAS/MAPK signaling.
RREB1 knockdown reduced proliferation and clonogenic
potential and reduced expression of cell cycle and DNA
replication genes. Our integrative analysis at 6p25.1
details increased binding of longer GGAA microsatellite
alleles with acquired EWSR-FLI1 to promote Ewing
sarcomagenesis by RREB1-mediated proliferation.},
keywords = {6p25.1 (Other) / EWSR1-FLI1 (Other) / Ewing sarcoma (Other)
/ GGAA microsatellite (Other) / GWAS (Other) / RREB1 (Other)
/ germline somatic interaction (Other) / long-read
sequencing (Other)},
cin = {B410 / HD01},
ddc = {570},
cid = {I:(DE-He78)B410-20160331 / I:(DE-He78)HD01-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36787739},
doi = {10.1016/j.ajhg.2023.01.017},
url = {https://inrepo02.dkfz.de/record/270998},
}